https://orcid.org/0000-0002-9087-8161
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Abstract
Introduction
Pancreatic cancer (PC) shows a very poor response to current treatments. Development of drug resistance is one of the causes of the therapy failure, being PARP1 (poly ADP-ribose polymerase 1) a relevant protein in the resistance mechanism. In this work, we have functionalized calcium phosphate-based nanoparticles (NPs) with Olaparib (OLA, a PARP-1 inhibitor) in combination with ascorbic acid (AA), a pro-oxidative agent, to enhance their individual effects.
Methods
Amorphous Calcium Phosphate (ACP) NPs were synthesized through a biomimetic approach and then functionalized with OLA and AA (NP-ACP-OLA-AA). After evaluation of the loading capacity and release kinetic, cytotoxicity, cell migration, immunofluorescence, and gene expression assays were performed using pancreatic tumor cell lines. In vivo studies were carried out on tumors derived from the PANC-1 line in NOD SCID gamma (NSG) mice.
Results
NP-ACP-OLA-AA was loaded with 13%wt of OLA (75% loading efficiency) and 1% of AA, respectively. The resulting dual nanosystem exhibited a gradual release of OLA and AA, being the latter protected from degradation in solution. This ensured the simultaneous availability of OLA and AA for a longer period, at least, during the entire time of in vitro cell experiments (72 hours). In vitro studies indicated that NP-ACP-OLA-AA showed the best cytotoxic effect outperforming that of the free OLA and a higher genotoxicity and apoptosis-mediated cytotoxic effect in human pancreatic ductal adenocarcinoma cell line. Interestingly, the in vivo assays using immunosuppressed mice with PANC-1-induced tumors revealed that NP-ACP-OLA-AA produced a higher tumor volume reduction (59.1%) compared to free OLA (28.3%) and increased the mice survival.
Conclusion
Calcium phosphate NPs, a highly biocompatible and biodegradable system, were an ideal vector for the OLA and AA co-treatment in PC, inducing significant therapeutic benefits relative to free OLA, including cytotoxicity, induction of apoptosis, inhibition of cell migration, tumor growth, and survival.
Graphical Abstract
Acknowledgments
This work has been carried out in the framework of the projects RYC2021-032734-I and PDC2022-133191-I00 (nanoSOP) funded by Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (MCIN/AEI/10.13039/501100011033) and the “European Union NextGenerationEU/PRTR”, and project PMPTA22/00136 funded by the Instituto de Salud Carlos III (FEDER). Support from the University of Granada and the Spanish Ministry of Universities under the program “María Zambrano” is also acknowledged.
Disclosure
All authors report a patent P202331095 pending to University of Granada. The authors report no other conflicts of interest in this work.